This study was aimed to observe the distribution of Mas-related G protein-coupled receptor A (MrgA) in cerebrospinal fluid (CSF)-contacting nucleus of normal rats and its expression in neuropathic pain, and to provide morphological evidence for CSF-contacting nucleus to participate in neuropathic pain. The model of neuropathic pain with chronic constriction injury (CCI) of the sciatic nerve was made in Sprague-Dawley rats. The thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) were measured. The expressions of MrgA in the CSF-contacting nucleus were examined by double labeling with immunofluorescent staining. The results showed that on the 5th, 7th, 10th and 14th days, the values of MWT and TWL in CCI group were all lower than those in sham group (P < 0.05). MrgA was found to be distributed in CSF-contacting nucleus of normal rats; and the expression was markedly up-regulated in rats at the peak of neuropathic pain. Our data suggest that CSF-contacting nucleus may participate in neuropathic pain through the MrgA-mediated signaling pathway.
Animals ; Neuralgia ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled/metabolism* ; Staphylococcal Protein A/metabolism* ; Up-Regulation

Animals ; Oocytes ; metabolism ; physiology ; Receptors, G-Protein-Coupled ; physiology ; Receptors, Purinergic P2X ; physiology ; Xenopus laevis

In growing children, growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest. Interestingly, one type of fracture injuries within the growth plate achieve amazing self-healing, however, the mechanism is unclear. Using this type of fracture mouse model, we discovered the activation of Hedgehog (Hh) signaling in the injured growth plate, which could activate chondrocytes in growth plate and promote cartilage repair. Primary cilia are the central transduction mediator of Hh signaling. Notably, ciliary Hh-Smo-Gli signaling pathways were enriched in the growth plate during development. Moreover, chondrocytes in resting and proliferating zone were dynamically ciliated during growth plate repair. Furthermore, conditional deletion of the ciliary core gene Ift140 in cartilage disrupted cilia-mediated Hh signaling in growth plate. More importantly, activating ciliary Hh signaling by Smoothened agonist (SAG) significantly accelerated growth plate repair after injury. In sum, primary cilia mediate Hh signaling induced the activation of stem/progenitor chondrocytes and growth plate repair after fracture injury.
Mice ; Animals ; Hedgehog Proteins/genetics* ; Receptors, G-Protein-Coupled/metabolism* ; Cilia/metabolism* ; Cartilage/metabolism* ; Regeneration

In this study, bioinformatics methods such as molecular docking and network pharmacology were adopted to establish Xiaoxuming Decoction (XXMD) "compound-vasodilatory and vasoconstrictory related G protein-coupled receptors (GPCR) targets" network, then the vascular function regulatory effective components and the potential targets of XXMD were analyzed. Based on the XXMD herb sources, the chemical structures of the compounds were retrieved from the national scientific data sharing platform for population and health pharmaceutical information center, TCMSP database and the latest research literatures. The chemical molecular library was established after class prediction and screening for medicinal and metabolic properties. Then, five kinds of vasodilatory and vasoconstrictory related GPCR crystal structure including 5-HT receptors (5-HT1AR, 5-HT1BR), AT1R, β2-AR, hUTR and ETB were retrieved from RCSB Protein Data Bank database or constructed by homology modeling of Discovery Studio 4.1 built-in modeling tools. After virtual screening by Libdock molecular docking, the highest rated 50 compounds of each target were collected and analyzed. The collected data were further used to construct and analyze the network by Cytoscape 3.4.0. The results showed that most of the chemical composition effects were associated with different vasodilatory and vasoconstrictory related GPCR targets, while a few effective components could be applied to multiple GPCR targets at the same time, therefore forming synergies and vasorelaxant effects of XXMD.
Databases, Protein ; Drugs, Chinese Herbal ; Models, Chemical ; Molecular Docking Simulation ; Receptors, G-Protein-Coupled ; metabolism ; Vasodilation

Based on the findings recently reported, cysteinyl leukotriene receptors, both CysLT (1) and CysLT(2) receptors, are involved in the ischemic and traumatic brain injury in vivo. CysLT(1)receptor regulates the increased permeability of blood-brain barrier and the related vasogenic brain edema, astrocyte proliferation, and inflammatory responses after brain ischemia; while CysLT(2)receptor regulates AQP4 expression and the related cytotoxic brain edema, and astrocyte injury. A new subtype of CysLT receptor, GPR17, is also involved in brain ischemic injury. The roles of CysLT receptors in brain injury or neuroprotection from the injury should be further understood. This understanding is necessary to accelerate the screening and development of the new drugs for the prevention and treatment of brain injury with the receptors as therapeutic targets.
Aquaporin 4 ; metabolism ; Brain Injuries ; metabolism ; Brain Ischemia ; metabolism ; Humans ; Receptors, G-Protein-Coupled ; metabolism ; Receptors, Leukotriene ; metabolism

G-protein-coupled receptor 17 (GPR17), an originally orphan receptor, was identified as a new uracil nucleotides/cysteinyl leukotriene receptor. However, whether GPR17 is really classified as a leukotriene receptor is a matter deserving further investigation. GPR17 is involved in many physiological and pathological processes including brain injury, spinal cord injury, and oligodendrocyte differentiation. GPR17 may become a new therapeutic target in these diseases. In this article, the research progress on the pharmacology and pathophysiological roles of GPR17 is reviewed.
Central Nervous System ; injuries ; physiopathology ; Humans ; Neurogenesis ; physiology ; Receptors, G-Protein-Coupled ; metabolism ; physiology

Hypertension is a clinical syndrome characterized by elevated systemic arterial blood pressure, which may be accompanied by functional or organic damage of heart, brain, kidney and other organs. The pathogenesis and development of hypertension are affected by genetic, environmental, epigenetic, intestinal microbiota and other factors. They are the result of multiple factors that promote the change of blood pressure level and vascular resistance. G protein coupled receptors(GPCRs) are the largest and most diverse superfamily of transmembrane receptors that transmit signals across cell membranes and mediate a large number of cellular responses required by human physiology. A variety of GPCRs are involved in the control of blood pressure and the maintenance of normal function of cardiovascular system. Hypertension contributes to the damages of heart, brain, kidney, intestine and other organs. Many GPCRs are expressed in various organs to regulate blood pressure. Although many GPCRs have been used as therapeutic targets for hypertension, their efficacy has not been fully studied. The purpose of this paper is to elucidate the role of GPCRs in blood pressure regulation and its distribution in target organs. The relationship between GPCRs related to intestinal microorganisms and blood pressure is emphasized. It is proposed that traditional Chinese medicine may be a new way to treat hypertension by regulating the related GPCRs via intestinal microbial metabolites.
Blood Pressure ; GTP-Binding Proteins ; Gastrointestinal Microbiome ; Humans ; Hypertension/genetics* ; Receptors, G-Protein-Coupled/metabolism*

OBJECTIVES: To identify the alternative splicing isoform of mouse sweet taste receptor T1R2, and investigate the effect of lipopolysaccharide (LPS) local injection on T1R2 alternative splicing and the function of sweet taste receptor as one of the bacterial virulence factors. METHODS: After mouse taste bud tissue isolation was conducted, RNA extraction and reverse transcription polymerase chain reaction (PCR) were performed to identify the splicing isoform of T1R2. Heterologous expression experiments RESULTS: T1R2 splicing isoform T1R2_Δe3p formed sweet taste receptors with T1R3, which could not be activated by sweet taste stimuli and significantly downregulated the function of canonical T1R2/T1R3. Local LPS injection significantly increased the expression ratio of T1R2_Δe3p in mouse taste buds. CONCLUSIONS LPS stimulation affects the alternative splicing of mouse sweet taste receptor T1R2 and significantly upregulates the expression of non-functional isoform T1R2_Δe3p, suggesting that T1R2 alternative splicing regulation may be one of the mechanisms by which microbial infection affects host taste perception.
Alternative Splicing ; Animals ; Lipopolysaccharides ; Mice ; Receptors, G-Protein-Coupled/metabolism* ; Taste ; Taste Buds

Trace amines are endogenous molecules distributed in the central nervous system and peripheral tissues that resemble common biogenic amines in terms of subcellular localization, chemical structure, and metabolism. Trace amine-associated receptor (TAAR) is a kind of evolutionarily conserved G-protein-coupled receptors in vertebrates, in which TAAR1 is a functional regulator of monoamine transmitters such as dopamine and serotonin. TAAR1 is widely considered as a potential therapeutic target for schizophrenia, depression and drug addiction. Moreover, TAAR1 is also expressed in peripheral tissues. The homeostasis imbalance of trace aminergic system can induce over-activation of peripheral immune system and central immune inflammatory response. TAAR1 modulators are becoming potential emerging drugs for the treatment of immune-related illnesses, because they may play a major role in the activation or modulation of immune response.
Animals ; Humans ; Receptors, G-Protein-Coupled/metabolism* ; Biogenic Amines ; Dopamine ; Substance-Related Disorders

Human salivary histatin 1 (Hst1) exhibits a series of cell-activating properties, such as promoting cell spreading, migration, and metabolic activity. We recently have shown that fluorescently labeled Hst1 (F-Hst1) targets and activates mitochondria, presenting an important molecular mechanism. However, its regulating signaling pathways remain to be elucidated. We investigated the influence of specific inhibitors of G protein-coupled receptors (GPCR), endocytosis pathways, extracellular signal-regulated kinases 1/2 (ERK1/2) signaling, p38 signaling, mitochondrial respiration and Na+/K+-ATPase activity on the uptake, mitochondria-targeting and -activating properties of F-Hst1. We performed a siRNA knockdown (KD) to assess the effect of Sigma-2 receptor (S2R) /Transmembrane Protein 97 (TMEM97)-a recently identified target protein of Hst1. We also adopted live cell imaging to monitor the whole intracellular trafficking process of F-Hst1. Our results showed that the inhibition of cellular respiration hindered the internalization of F-Hst1. The inhibitors of GPCR, ERK1/2, phagocytosis, and clathrin-mediated endocytosis (CME) as well as siRNA KD of S2R/TMEM97 significantly reduced the uptake, which was accompanied by the nullification of the promoting effect of F-Hst1 on cell metabolic activity. Only the inhibitor of CME and KD of S2R/TMEM97 significantly compromised the mitochondria-targeting of Hst1. We further showed the intracellular trafficking and targeting process of F-Hst1, in which early endosome plays an important role. Overall, phagocytosis, CME, GPCR, ERK signaling, and S2R/TMEM97 are involved in the internalization of Hst1, while only CME and S2R/TMEM97 are critical for its subcellular targeting. The inhibition of either internalization or mitochondria-targeting of Hst1 could significantly compromise its mitochondria-activating property.
Endocytosis/physiology* ; Histatins/pharmacology* ; Humans ; Membrane Proteins ; Mitochondria/metabolism* ; RNA, Small Interfering/pharmacology* ; Receptors, G-Protein-Coupled/metabolism* ; Receptors, sigma